Category Archives: Drugs for Diabetes

Type 2 Diabetes: Major Health Benefit From Drugs That Don’t Cause Hypoglycemia

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A recent study looked at the health benefits of type 2 diabetes drugs, comparing drugs that can cause hypoglycemia and those that don’t. The very first sentence of the abstract didn’t give me much hope for what followed. That sentence was: “Different guidelines provide similar, but not identical, therapeutic targets for HbA1c in type 2 diabetes. These targets can also depend from the different pharmacological strategies adopted for intensifying glycemic control.” Did you catch the misprint?

This meta-analysis of 13 clinical trials was looking for differences in various health outcomes over the course of at least two years, comparing successful intensive management to standard care or placebo. Successful intensive management was defined as at least a 0.5% (6 mmol/mol) improvement in hemoglobin A1c (HgbA1c) level. “Intensification” of drug therapy is usually applied to a patient who is not at goal HgbA1c level. Undoubtedly, the benefits of intensification will be greater for those at HgbA1c of 10% than for those at 7.5%. BTW, few large clinical trials include patients over 75 years of age.

For my U.S. readers, note that other countries often specify HgbA1c values as mmol/mol instead of %. And blood sugars are not our usual mg/dl, but instead reported as mmol/l. HbA1c of 7% equals 53 mmol/mol, which would indicate and average blood sugar of 154 mg/dl or 8.6 mmol/l. As another example, HbA1c of 6.5% is 48 mmol/mol, reflecting average blood sugar of 140 mg/dl or 7.8 mmol/l. Are you thoroughly confused yet?

In the general population, lowest levels of mortality are seen at HgbA1c’s around 5 to 5.5% (31 to 36.6 mmol/mol). The average healthy non-diabetic adult hemoglobin A1c is 5% (31 mmol/mol) and translates into an average blood sugar of 100 mg/dl (5.56 mmol/l). This will vary a bit from lab to lab. Most healthy non-diabetics would be under 5.7% (38.8 mmol/mol). In December, 2009, the American Diabetes Association established a hemoglobin A1c criterion for the diagnosis of diabetes: 6.5% (47.5 mmol/mol) or higher. Diagnosis of prediabetes involves hemoglobin A1c in the range of 5.7 to 6.4% (38.8 to 46.5 mmol/mol).

Some expert panels recommend aiming for HgbA1c under 7% (53 mmol/mol), others recommend under 6.5% (48 mmol/mol). A major point of debate between the two guideline goals, is that the lower you set the goal, the greater the risk of drug-induced hypoglycemia, which can be lethal. In the early 1980s, the only drugs we had for diabetes were insulin, sulfonylureas, and metformin. Two of those three can can cause hypoglycemia. Now, a majority of our type 2 diabetes drugs don’t cause hypoglycemia.

If you’re at risk for hypoglycemia, teach those you hang with how to recognize and treat it

The Italian researchers did this meta-analysis as part of their effort to produce diabetes drug treatment guidelines for the Italian population. On to the study at hand…

What Did the Researchers Find?

Improved glycemic (blood sugar) control by intensive attention reduced the major cardiovascular event rate by 10% and reduced renal adverse events by 25% but did not affect overall mortality or eye complications.

Intensified therapy with hypoglycemia-inducing drugs did not reduce overall mortality.

Drugs without potential for causing hypoglycemia were linked to lower risk of major cardiovascular events, kidney adverse events, and overall mortality, for HgbA1c under 7% (53 mmol/mol).

In conclusion, the results of this meta-analysis of RCTs show that in people with T2DM the improvement of glycemic control with drugs not inducing hypoglycemia is associated with a reduction in the risk of long-term chronic vascular complications (major adverse cardiac events and renal adverse events) and all-cause mortality, at least for HbA1c levels above 7%. The reduction of HbA1c below that threshold could have some favorable effects, but there is no available direct evidence in this respect. When the reduction of HbA1c is achieved with drugs inducing hypoglycemia, a progressive reduction of complications and an increase in the risk of severe hypoglycemia is observed. Therefore, the choice of the most adequate HbA1c target for each patient with T2DM should be made considering an appropriate risk/benefit ratio.

Full text in Nutrition, Metabolism & Cardiovascular Diseases.

I think the researchers were particularly glad to find that intensification of drug therapy can reduce risk of heart attack, stroke, kidney complications, and death; all this without the risk of hypoglycemia that comes with drugs like insulin and sulfonylureas. The lack of a mortality benefit from hypoglycemia-inducing drugs may also be important. The benefits of intensive drug therapy (or lack thereof) depend somewhat on the particular complication you’re trying to avoid, and on baseline HgbA1c. Drug therapy is complicated! I expect these researchers would recommend a treatment HgbA1c goal of <7% rather than <6.5%.

Steve Parker, M.D.

PS: Reduce your need for diabetes drugs by losing excess weight, exercising, and eating low-carb.

Finerenone: New Drug to Prevent Chronic Kidney Disease and Cardiovascular Death in Type 2 Diabetes

Verbatim from the FDA press release:

FDA has approved Kerendia (finerenone) tablets to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalization for heart failure in adults with chronic kidney disease associated with type 2 diabetes.

Diabetes is the leading cause of chronic kidney disease and kidney failure in the United States. Chronic kidney disease occurs when the kidneys are damaged and cannot filter blood normally. Because of defective filtering, patients can have complications related to fluid, electrolytes (minerals required for many bodily processes), and waste build-up in the body. Chronic kidney disease sometimes can progress to kidney failure. Patients also are at high risk of heart disease.

The efficacy of Kerendia to improve kidney and heart outcomes was evaluated in a randomized, multicenter, double-blind, placebo-controlled study in adults with chronic kidney disease associated with type 2 diabetes. In this study, 5,674 patients were randomly assigned to receive either Kerendia or a placebo.

The study compared the two groups for the number of patients whose disease progressed to a composite (or combined) endpoint that included at least a 40% reduction in kidney function, progression to kidney failure, or kidney death. Results showed that 504 of the 2,833 patients who received Kerendia had at least one of the events in the composite endpoint compared to 600 of the 2,841 patients who received a placebo.

The study also compared the two groups for the number of patients who experienced cardiovascular death, a non-fatal heart attack, non-fatal stroke, or hospitalization for heart failure. Results showed that 367 of the 2,833 patients receiving Kerendia had at least one of the events in the composite endpoint compared to 420 of the 2,841 patients who received a placebo, with the treatment showing a reduction in the risk of cardiovascular death, non-fatal heart attack, and hospitalization for heart failure.

Side effects of Kerendia include hyperkalemia (high levels of potassium), hypotension (low blood pressure), and hyponatremia (low levels of sodium). Patients with adrenal insufficiency (when the body does not produce enough of certain hormones) and those receiving simultaneous treatment with strong CYP3A4 inhibitors should not take Kerendia.

Kerendia received priority review and fast track designations for this application.

FDA granted the approval of Kerendia to Bayer Healthcare.


Click for prescribing information.


Parker here.

Just offhand, finerenone doesn’t look like a great drug. Helpful, maybe. Chronic kidney disease can end up at ESRD (end stage renal disease), which requires thrice weekly hemodialysis if the patient wants to stay alive. (Yes, peritoneal dialysis is an alternative.) Preventing ESRD is an incredible benefit for an individual.

Finerenone seems to be a well-tolerated daily pill. The main adverse effect is elevated blood potassium level, which can cause palpitations, and death infrequently. Less commonly, the drug can cause low blood pressure.

The ultimate role of finerenone in our armamentarium against disease and suffering will probably depend on cost and the number needed to treat.

Steve Parker, M.D.

Is Biden Responsible for the High Cost of Insulin?

Hamburger-Avocado Salad with tomatoes, cucumbers, lettuce, salt/pepper, and olive oil vinaigrette

Newsweek looks at the issue.

In any case, why not reduce your need for insulin with low-carb eating?

Steve Parker, M.D.

How to Save $ on Your Diabetes Drugs

This Shrimp Salad is low-carb. Use the search box for recipe.

Christine Fallabel has an article at Diabetes Daily that may save you beaucoup bucks on your diabetes care, whether or not you have insurance coverage.

If you live in a country like the United States, where the majority of health insurance is privatized and there is no strong social safety net, it can feel as though managing a chronic disease like diabetes requires nothing but lots of money. And it does. As of 2017, diabetes cost the United States a staggering $327 billion dollars per year on direct health care costs, and people with diabetes average 2.3x higher health care costs per year than people living without the disease.

Diabetes is also devastatingly expensive personally: the cost of insulin has risen over 1200% in the past few decades, with no change to the chemical formula. In 1996, when Eli Lilly’s Humalog was first released, the price for a vial of insulin was $21. In 2019, that same vial costs around $275. Studies show that 1 in 4 people ration insulin simply due to cost. Diabetes Daily recently conducted a survey study, with almost 2,000 participants, of which an overwhelming 44% reported  struggling to afford their insulin.

So where does this leave patients who don’t have tons of money to spend on insulin and supplies, or who don’t have adequate health insurance coverage for the technology to help prevent complications? Can you manage diabetes well without lots of money? The short answer is yes. The long answer is a bit more complicated.

Source: Can You Manage Diabetes Well Without Lots of Money? – Diabetes Daily

Steve Parker, M.D.

PS: A low-carb paleo diet will also reduce your drug costs. 

PPI Drugs Linked to Doubled Risk of #COVID19

Click for details.

You should assume there’s a good reason or two why we have acidic stomach juice. One reason is to prevent infection.

I see two many patients who are put on these drugs are a good reason, but they keep taking them after the drug has finished it’s job.

An “as needed” H2 blocker like Pepcid may be a reasonable substitute for PPIs. Check with your personal physician.

I have nothing against Prilosec in particular. It can be very helpful. It’s one of several PPIs on the market.

Steve Parker, M.D.

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Metformin: More Than Just a Diabetes Drug?

Metformin? A shirt from 1967?

Medical Xpress has an article about the possible future uses of metformin for weight loss, prostate cancer treatment, and tuberculosis treatment. It didn’t mention metformin as an anti-aging drug.

From the article:

Among medications, metformin has a long and storied past. The compound destined to become metformin was first isolated during the Middle Ages from the French lilac, a plant scientifically known as Galega officinalis. Ground flowers and leaves were administered by healers to patients suffering from constant urination, a hallmark of a disorder that later would become known as diabetes. The active ingredient in French lilac, a plant also called goat’s rue, was identified hundreds of years later as galegine, which triggered a striking reduction in blood glucose.

By the 1950s, scientists were able to exploit folk medicine uses and develop the drug that became metformin.

Source: Wonder drug? Exploring the molecular mechanisms of metformin, a diabetes drug with Medieval roots

Don’t believe everything you read. The article claims metformin’s effectiveness in type 2 diabetes is primarily due to weight loss. Conventional thinking is that it’s mostly due to decreased production and release of glucose by the liver. I guess time will tell which theory wins out. In either case, it’s a good initial drug for T2 diabetes if diet and exercise prove inadequate.

Steve Parker, M.D.

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Dietary Fat Influences Insulin Requirements in Type 1 Diabetes

Is this pane di casa?

Everyone with diabetes—whether type 1 or type 2—should know that the amount of carbohydrate in meals has an impact on blood sugar levels and insulin requirements. In general, the more carbs, the more insulin you need, whether that insulin comes from a pharmacy or your pancreas. Less well known is that dietary protein and fat also have an effect on insulin requirements. It’s complicated, and there’s quite a bit of variation from one individual to another. The study at hand involved folks with type 1 diabetes using an insulin pump. The test meal was a piece of bread (pane di casa, 45 g carb) plus avocado and other fats in varying amounts.

From Diabetes Care:

The current study has two important outcomes. First, the type of fat has no statistically or clinically significant impact on postprandial glycemia, but the amount of fat has a significant, dose-dependent effect. Second, the insulin delivery pattern, and in some cases total dose, needs to be adjusted based on the amount of fat in order to minimize the risk of early postprandial hypoglycemia and late postprandial hyperglycemia.

Source: Amount and Type of Dietary Fat, Postprandial Glycemia, and Insulin Requirements in Type 1 Diabetes: A Randomized Within-Subject Trial | Diabetes Care

Steve Parker, M.D.

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Ketogenic and Very Low-Carb Diet Effective for T2 Diabetes for at Least Two Years

This Avocado Chicken soup is very low-carb. Use the search box to find the recipe.

It’s well-established that very low-carb and ketogenic diets over the short-term usually do a good job for folks with type 2 diabetes: better blood sugar levels, fewer diabetes drugs needed, improved lipids, lower blood pressure, etc. Many people—from patients to dietitians to physicians—question whether the diet and associated improvements can be sustained for more than a few months. The study at hand looked at results two years out, and found definite clinical benefit and sustainability.

First, a quick point to get out of the way. In the U.S., HgbA1c is reported as a percentage. But other countries often report HgbA1c in mmol/mol. It’s not easy to convert one to the other accurately, so when you see values in mmol/mol below, be aware they’re only my approximations, not the researchers’.

Here’s how the researchers did their study, published in the summer of 2019.

Scientific Method

262 adults with type 2 diabetes (average age 54) were enrolled in the intervention group, called CCI (digitally-monitored continuous care intervention via a web-based app). 87 were assigned to “usual care.” For all participants at baseline, body mass index averaged 37-40, HgbA1c averaged 7.6% (60 mmol/mol), and they had diabetes for an average of eight years. The CCI group monitored beta-hydroxybutyrate (a ketone) levels, glucoses, body weight, etc, and uploaded results via the web-based app. The app also facilitated an online peer community for social support. For those who preferred in-person education (about half of the total), clinic-based group meetings were held weekly for 12 weeks, bi-weekly for 12 weeks, monthly for six months, and then quarterly in the second year. Continuous Care Intervention included individual support with telemedicine, customized nutritional guidance (emphasis on sustained nutritional ketosis), and health coaching.

The 87 Usual Care folks were recruited from the same geographic area and healthcare system. The received care from their primary care physician or endocrinologist and were counseled by a dietitian (ADA recommendations) as part of their diabetes education. Medical care was not modified for the study. This group had less intense clinical measurements than the CCI cohort.

Of the 262 participants who started with the CCI group, 218 remained after one year. So 44 drop-outs. Of these 262 pioneers, 194 remained for the entire second year (so 24 more drop-outs). If those drop-out numbers seem high to you, be aware that they are NOT. Even the Usual Care group of 87 had 19 drop-outs over the two years.

So what happened?

Reductions from baseline to two years in the CCI group included: fasting insulin, weight (down about 10% or 11.9 kg), blood pressure (systolic and diastolic), HgbA1c, and triglycerides. Those are all going in the right direction.

Other findings for the CCI group: HDL-cholesterol (“good cholesterol”) went up. Excluding metformin, the use of diabetes control drugs in the CCI group dropped from 56% of participants to 27%. Some dietitians fear the ketogenic diets are bad for bones, causing calcium to leak out of bones, weakening them since calcium is the main mineral in bones. But spine bone mineral density in the CCI group was unchanged over the two years.

The “usual care” group had no changes in those measurements or diabetes medication use.

Now, to understand some of the investigators results, you need to know their definitions. Diabetes remission = glycemic control without medication use. Partial remission is “sub-diabetic hyperglycemia of at least 1 year duration, HgbA1c level between 5.7-6.5% (39 to 48 mmol/mol), without any medications (two HbgA1c measurements).” Complete remission is “normoglycemia of at least 1 year duration, HgbA1c below 5.7% [39 mmol/mol], without any medications (two HgbA1c measurements).” Diabetes reversal per Supplementary Table 2: Sub-diabetic hyperglycemia and normoglycemia (HgbA1c below 6.5% or 48 mmol/mol), without medications except metformin.

The CCI group had resolution of diabetes (partial or complete remission in 18%, reversal in 53%), which was not seen in the usual care group. Complete remission was achieved in 17 (6.7%) of the CCI group. HgbA1c in the CCI group at two years dropped from average of 7.6% (60 mmol/mol)  to 6.7% (50 mmol/mol).

Conquer Diabetes and Prediabetes

Metformin is the most-recommended drug for type 2 diabetes

“CCI diabetes reversal exceeds remission as prescriptions for metformin were usually continued given its role in preventing disease progression, preserving beta-cell function and in the treatment of pre-diabetes per guidelines.”

The average dose of insulin in CCI folks who were using insulin at baseline decreased by 81% at two years. (Have you noticed the price of insulin lately?)

Beta-hydroxybutyrate is a ketone, and at a certain level in the blood, indicates the presence of ketosis on a ketogenic diet. “The 2 year beta-hydroxybutryate (BHB) increase above baseline demonstrated sustained dietary modification.”  “…the encouraged range of nutritional ketosis (> or = 0.5 mM) was observed in only a minority (14.1%) of participants at 2 years. On average, patient-measured BHB was > or = 0.5mM for 32.8% of measurement over the 2 years.”

Bottom Line

In summary, the CCI group—eating ketogenic and/or very low-carb—showed sustained beneficial effects even two years after start of the study. I suspect the Virta app, clinic-based group meetings, and individual support and coaching contributed significantly to the participants’ success.

Steve Parker, M.D.

PS: By the way, many of the study authors are affiliated with Virta Health Corp., which I assume is a for-profit company. Virta provided funding for the study. Could that funding have unduly influenced the results? It’s always possible but I have no evidence that it did. If not already available, I expect a commercial version of the program will be within 12–24 months.

Reference: Athinarayanan, S.J., et al (including Sarah Hallberg, Jeff Volek, and Stephen Phinney). Long-Term Effects of a Novel Continuous Remote Care Intervention Including Nutritional Ketosis for the Management of Type 2 Diabetes: A 2-year Non-randomized Clinical Trial. Frontiers in Endocrinology, Vol. 10, article 348, June 19, 2019.

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Particular Diabetes Drugs May Protect Your Heart and Kidneys

 

Blood pressure control is also extremely important for protection of heart and kidneys

I’ve been reticent to tout the putative heart-protective effects of diabetes drugs in the classes called SGLT2 inhibitors and GLP-1 receptor agonists. Frankly, their supposed kidney-protective effects haven’t even been on my radar. My hesitation to report on these matters stems from:

Maybe if Big Pharma sent me a nice check….

The GLP-1 receptor agonists seem to have beneficial effects on both heart and kidney. With SGLT2 inhibitors, renal benefits may be more prominent than cardiac. Also note that any beneficial heart or renal effects may be attributable only to certain drug within the class, and not a class effect.

For what it’s worth, the American Diabetes Association recently hosted a conference on these issues. I assume the ADA endorses the report written by three experts, two of whom have received some sort of compensation from pharmaceutical companies. This doesn’t necessarily mean they are biased. Some excerpts:

Since patients with diabetes are at increased risk for CV [cardiovascular] and renal events, reducing the risk of these events is of primary interest to improve outcomes in the long-term. [Cardiovascular events usually refers to heart attacks, strokes, and death from those. Renal events would be high loss of protein through the kidneys, impaired kidney function or chronic kidney disease, or the need for dialysis.]

SGLT2 inhibitors and GLP-1 RAs have dramatically changed the treatment landscape of type 2 diabetes due to their established CV benefits, and the observed improvements in renal function seen with these classes of agents are currently undergoing intense investigation.

***

It is now apparent that both SGLT2 inhibitors and GLP-1 RAs show consistent reductions in major adverse cardiovascular events for patients with established cardiovascular (CV) disease, and both appear to have renal benefits as well.

***

The nephron is the microscopic structural and functional unit of the kidney.

Renal effects of GLP-1 receptor agonists

These drugs may exert their beneficial actions on the kidneys through their effects on lowering blood glucose and blood pressure and by reducing the levels of insulin.

For GLP-1RAs, these [studies] include ELIXA with lixisenatide, LEADER with liraglutide, SUSTAIN-6 with semaglutide, EXCSEL with exenatide once-weekly, HARMONY with albiglutide, and REWIND with dulaglutide.

All these studies indicate that albuminuria [protein loss through urine] is reduced during treatment with GLP-1 RAs, and eGFR [estimated glomerular filtration rate, a measure of kidney function] appears to be stabilized.

These benefits are seen independently of HbA1c, weight, and blood pressure variations.

***

Heart attack is only one type of cardiovascular event

Cardiovascular effects of GLP-1 receptor agonists

Large CV outcomes trials with GLP-1 RAs have shown that these agents can reduce the risk of major adverse CV events, CV mortality, and all-cause mortality.

These CV benefits appear to be related to four distinct mechanisms:

    • Improve myocardial [heart muscle] performance in ischemic heart failure [caused by poor blood flow to heart]
    • Improve myocardial survival in ischemic heart disease
    • Ameliorate endothelial dysfunction [endothelium is the lining of arteries]
    • Decrease markers of CV risk.

***

Renal effects of SGLT2 inhibitors

  • However, many potential mechanisms have been linked to the renoprotective effects of SGLT2 inhibitors.
  • These include reduction of blood pressure, improved metabolic parameters, reduced volume overload, reduction in albuminuria, and glomerular pressure.
  • For the latter, SGLT2 inhibition appears to reduce hyperfiltration via a tubuloglomerular feedback mechanism.
  • Clinical data from CV outcomes trials have shown consistent variations in eGFR and reduction in death from renal causes with empagliflozin, canagliflozin, and dapagliflozin.
  • However, to gain more information about the renal effects of these agents, dedicated renal outcomes trials are needed to study reductions in albuminuria, changes in eGFR, number of patients reaching end-stage renal disease, need for dialysis, and deaths due to kidney failure.

***

Key Messages from the authors

Large CV outcomes trials have shown that both SGLT2 inhibitors and GLP-1 RAs are associated with significant reductions in CV events in patients with elevated CV risk.

From CV outcomes trials both classes of agents also appear to have renal benefits, although large dedicated studies are needed to establish the magnitude of this potential benefit

The mechanism of action at the basis of CV and renal benefits of SGLT2 inhibitors and GLP-1 RAs is complex, multifactorial, and still not completely understood.

I’m still skeptical but will keep an open mind.

Steve Parker, M.D.

PS: Bold emphasis above is mine.

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Review Article Supports Tight Control in Diabetes

What are reasonable blood sugar and HgbA1c goals for folks with diabetes? The experts continue to debate. If I had diabetes, I’d want my glucose levels as close to normal as possible. On the other hand, if I had terminal cancer, I’d be fine with higher levels.

In Diabetes Care:

Glycated hemoglobin targets have been given in guidelines for the last three decades, mostly without change at around 6.5–7.0% (47–53 mmol/mol). Personalization of such targets has also long been advocated, but often with little and inappropriate guidance. More recently some have suggested higher targets might be indicated, and more specifically lower targets avoided, even in those in whom they are easily attained without seeming burden or risk. Prospective data from randomized and observational studies, in people with type 2 diabetes and indeed those without diabetes, find cardiovascular and mortality risk are uniformly lowest at lower levels including into the normal range. In some studies with large populations, a high proportion of people are found to attain such levels, and the UK Prospective Diabetes Study (UKPDS) and more recent studies appear to confirm the importance of starting low and continuing long. Studies of cardiovascular events and mortality in people with diabetes will already factor in any effect of hypoglycemia, which therefore should not be double-counted in setting targets. Nevertheless, some factors should lead to modification of target levels, and these will include experience of hypoglycemia where therapy change and glucose monitoring cannot ameliorate it and sometimes prospectively in those at social or occupational risk. The fact that clinical experience will modify targets emphasizes that targets will not be stable over time but will change, for example, with occurrence of adverse events or perceptions of increase/decreased burden of therapy. The evidence suggests that glucose control takes 5 years or more to have any impact on vascular outcomes or mortality, so targets may also be higher in those with shorter life expectancy or higher health burden or simply reflect individual preferences. This article discusses the evidence behind these conclusions.

Source: Controversies for Glucose Control Targets in Type 2 Diabetes: Exposing the Common Ground | Diabetes Care

Steve Parker, M.D.

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